This application is a 371 of PCT/EP00/12009 filed Nov. 29, 2000.
The present invention is in the field of steroid compounds having a cyclopropane ring, which ring includes carbon atoms 14 and 15 of the steroid skeleton. More particularly, the invention pertains to such steroid compounds as possess an androgenic activity.
Steroids having the above-indicated cyclopropane ring have been disclosed in EP 768 316, which is in the field of female contraception and hormone-therapy against endometriosis or climacteric complaints. The steroids are described as having progestagenic activity, examples being 14xcex1,15xcex1-methylene estra-4,9-diene-3-one-17xcex1-ol and 3-oxo 14xcex2,15xcex2-methylene estra-4,9-diene-17xcex2-yl (N-phenyl)carbamate. Neither potency, nor any other receptor activities, of these progestagens can be derived from this disclosure.
In a non-prepublished patent application PCT/DE99/01795 (published on Dec. 29, 1999 as WO 99/67276) a group of 14,15-cyclopropyl steroids has been described, among which are 17xcex2-hydroxy substituted ones.
Another non-prepublished patent application is WO 00/53619 wherein a group of androgenic steroids is described which have a 14xcex2,17xcex1 configuration, viz. (14xcex2,17xcex1)-17-(hydroxymethyl) steroids.
The present invention now provides a novel group of steroids of the general type as indicated above, which possess an unexpected androgenic activity. Distinct from the progestagens disclosed in the art, the androgens of the present inventionxe2x80x94including very potent onesxe2x80x94int.al. satisfy the requirements that the cyclopropane ring is xcex2-oriented and that on carbon atom no. 17 a hydroxymethyl group is present which is xcex1-oriented. As a consequence, the steroids of the invention have the 14xcex2-configuration, contrary to natural steroid hormones, such as testosterone and estradiol, which have a configuration 14xcex1, 17xcex2.
The steroids according to the invention satisfy the structural formula I: 
wherein
R1 is O, (H,H), (H,OR), NOR, with R being hydrogen, (C1-6) alkyl, (C1-6) acyl;
R2 is hydrogen, or (C1-6) alkyl;
R3 is hydrogen; or R3 is (C1-6) alkyl, (C2-6) alkenyl, or (C2-6) alkynyl, each optionally substituted by halogen;
R4 is hydrogen, (C1-6) alkyl, or (C2-6) alkenyl;
R5 is (C1-6) alkyl;
R6 is hydrogen, halogen, or (C1-4) alkyl;
R7 is hydrogen, or (C1-6) alkyl;
R8 is hydrogen, hydroxy, (C1-6) alkoxy, halogen, or (C1-6) alkyl;
R9 and R10 are independently hydrogen; or R9 and R10 are independently (C1-6)alkyl, (C2-6) alkenyl, (C3-6) cycloalkyl, (C5-6) cycloalkenyl, or (C2-6) alkynyl, each optionally substituted by (C1-4) alkoxy, or halogen;
R11 is hydrogen, SO3H, (C1-15) acyl; and the dotted lines indicate optional bonds, selected from a xcex944, xcex945(10), or xcex9411 double bond, or a xcex944.9 or xcex944.11 diene system.
The invention not only pertains to steroids which satisfy structural formula I, but also to pharmaceutically acceptable salts or esters, prodrugs and precursors thereof.
The term (C1-6) alkyl as used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms, like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Likewise, the term (C1-4) alkyl means an alkyl group having 1-4 carbon atoms. Preferred alkyl groups have 1-4 carbon atoms, and most preferred alkyl groups are methyl and ethyl.
The term (C2-6) alkenyl means a branched or unbranched alkenyl group having at least one double bond and 2-6-carbon atoms. Preferred alkenyl groups have 2-4 carbon atoms, such as vinyl and propenyl.
The term (C2-6) alkynyl means a branched or unbranched alkynyl group having at least one triple bond and 2-6 carbon atoms. Preferred alkynyl groups have 2-4 carbon atoms, such as ethynyl and propynyl.
The term (C3-6) cycloalkyl means a cycloalkane ring having 3-6 carbon atoms, like cyclopropane, cyclobutane, cyclopentane and cyclohexane.
The term (C5-6) cycloalkenyl means a cycloalkene ring having at least one double bond and 5 or 6 carbon atoms.
The term (C1-6) alkoxy means a branched or unbranched alkyloxy group having 1-6 carbon atoms, like methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tertiary butyloxy, pentyloxy, and hexyloxy. Likewise, the term (C1-4) alkoxy means a branched or unbranched alkyloxy group having 1-4 carbon atoms. Preferred alkyloxy groups have 1-4 carbon atoms, and most preferred is methyloxy.
The term (C1-6) acyl means an acyl group derived from a carboxylic acid having 1-6 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, and hexanoyl. Likewise, the term (C1-15) acyl means an acyl group derived from a carboxylic acid having 1-15 carbon atoms. Also included within the definition of (C1-6) acyl or (C1-15) acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on.
The term halogen means fluorine, chlorine, bromine, or iodine. When halogen is a substituent at an alkyl group, like in the definition R3, R6, R8, R9 and R10, Cl and F are preferred, F being most preferred.
The 14xcex2,15xcex2-methylene-17xcex1-methanol steroid derivatives of this invention have the natural configurations 5xcex1, 8xcex2, 9xcex1, 10xcex2, and 13xcex2. The configuration at C-17 is 17xcex1. The compounds of the invention may possess also one or more additional chiral carbon atoms. They may therefore be obtained as a pure diastereomer, or as a mixture of diastereomers. Methods for obtaining the pure diastereomers are well known in the art, e.g. crystallization or chromatography.
For therapeutic use, salts of the compounds of formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of the acids according to formula I may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention. Examples of salts of acids according to the invention are mineral salts such as sodium salt, potassium salt, and salts derived from organic bases like ammonia, imidazole, ethylenediamine, triethylamine and the like.
The compounds of the invention as described hereinbefore in general possess an unexpected androgenic activity. Androgenic activity can be measured in various ways. Thus, the potency of androgens can be determined in vitro using the cytoplasmic androgen receptor from human breast tumor cells (MCF-7 cell line); see Bergink, E. W. et al, Comparison of the receptor binding properties of nandrolone and testosterone under in vitro and in vivo conditions, J. Steroid Biochem. 22, 831-836 (1985). It is also possible to use Chinese hamster ovary (CHO) cells transfected with the human androgen receptor (incubation time 16 h, temperature 4xc2x0 C.) and compared with the affinity of 5xcex1-dihydrotestosterone [according to the procedure described by Bergink, E. W. et al, J. Steroid Biochem. 19, 1563-1570 (1983)]. The transactivative androgen activity of the compounds of the invention can be measured, e.g. in Chinese hamster ovary cells (CHO) transfected with the human androgen receptor (hAR), in combination with a mouse mammary tumor virus (MMTV), and luciferase receptor gene (incubation time 16 h, temperature 37xc2x0 C.) and compared with the activity of 5xcex1-dihydrotestosterone [according to the procedure described by Schoonen, W. G. E. J. et al, Analyt. Biochem. 261, 222-224 (1998)]. For the in vivo potency determination of androgens the classical Hershberger test can be used. In this test the androgenic (increase in prostate weight) and anabolic activities [increase of the musculus levator ani (MLA)] of a compound are tested in immature castrated rats after daily administration for 7 days; see Hershberger, L. G. et al, Myotrophic activity of 19-Nortestosterone and other steroids determined by modified levator ani muscle method, Proceedings of the society for experimental biology and medicine 83, 175-180 (1953). Additionally, the effect of an androgenic compound on LH suppression can be tested in mature castrated rats according to Kumar, N. et al, The biological activity of 7alpha-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone, Endocrinology 130, 3677-3683 (1992).
The preference goes to those compounds according to the invention which exhibit a relatively high androgenic activity. Thus, the preferred compounds of the invention are those satisfying the above structural formula I, wherein R1 is oxo, and the dotted lines indicate a xcex944 double bond. More preferred are compounds wherein R3 is 7xcex1-methyl. A specifically preferred compound of the invention is (7xcex1,14xcex2,15xcex2,17xcex1)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one.
As androgenic hormones the steroids of the present invention can be used in, inter alia, male contraception and male HRT (hormone replacement therapy). Thus, e.g. male contraception may comprise a regimen of administration of hormones in which a progestagen serves to achieve a contraceptive effect and an androgen serves to supplement the resulting decreased testosterone level. Another option is that male contraception is performed with an androgenic hormone alone. The androgens can also be used for androgen supplementation in the partially androgen deficient ageing male. Next to the use in the male, the androgens of the invention also can be used in the female, e.g. as androgen replacement therapy in postmenopausal women, or in androgen-deficient children.
The present invention also relates to a pharmaceutical composition comprising a steroid compound according to the invention mixed with a pharmaceutically acceptable auxiliary, such as described in the standard reference, Gennaro et al, Remmington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). The mixture of the steroid compounds according to the invention and the pharmaceutically acceptable auxiliary may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. The steroid compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts.
Furthermore, the invention relates to the use of the steroid compound according to the invention for the manufacture of a medicament in the treatment of androgen-deficiency, such as in male or female HRT (hormone replacement therapy). Accordingly, the invention also includes a method of treatment in the field of male or female HRT, comprising the administration to a male or female patient suffering from an androgen-deficiency, of a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
Further, the invention relates to the use of a steroid compound according to the invention for the manufacture of a medicament having contraceptive activity (for which in the art the term xe2x80x9ccontraceptive agentxe2x80x9d is also used). Thus the invention also pertains to the medical indication of contraception, i.e. a method of contraception comprising the administration to a subject, being a male, preferably a human male, of a compound as described hereinbefore (in a suitable pharmaceutical dosage form), in combined therapy with a progestagen or not.
The androgens according to the invention can also be used in a kit for male contraception. Although this kit can comprise one or more androgens only, it is preferred that it comprises means for the administration of a progestagen and means for the administration of an androgen.
The latter means is a pharmaceutical formulation comprising compound according to the invention as described hereinbefore, and a pharmaceutically acceptable carrier.
The invention also pertains to a method of treatment comprising administering to a (notably human) male or female in need of androgen-supplementation a therapeutically effective amount of a 14xcex2,15xcex2-methylene-17xcex1-methanol steroid derivative as described hereinbefore. This is irrespective of whether or not the need for androgen-supplementation has arisen as a result of male contraception involving the administration of a sterilitant, such as a progestagen.
Further, the invention pertains to a method of contraception, comprising administering to a fertile male, notably human, a 14xcex2,15xcex2-methylene-17xcex1-methanol steroid derivative as described hereinbefore in a dosage amount and regimen which is sufficient for said compound to be contraceptively effective per se. Alternatively, the method of contraception provided by the present invention comprises administering to a fertile male, notably human, a contraceptively effective combination of a sterilitant, such as a progestagen, and a 14xcex2,15xcex2-methylene-17xcex1-methanol steroid derivative as described hereinbefore.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids (see, for example: Fried, J. et al, Organic Reactions in Steroid Chemistry, Volumes I and II, Van Nostrand Reinhold Company, New York, 1972). Essential is the introduction of a 14xcex2,15xcex2-methylene group and a (substituted) 17xcex1-(hydroxymethyl) group to the steroid nucleus.
A convenient starting material for the preparation of compounds of formula I wherein R1 is oxo; R2, R7, R8 and R11 are hydrogen; R3 and R4 are hydrogen or (C1-6) alkyl; R5 is methyl; R6, R9 and R10 have the previously given meaning; and the dotted lines indicate a xcex944 double bond, is for instance a compound of general formula II, wherein R3 and R4 are hydrogen or (C1-6) alkyl, whose synthesis is known in literature, or which can be prepared using standard methods [see e.g. U.S. Pat. No. 3,407,217 (1965; R3xe2x95x90H, R4xe2x95x90H), FR 1434172 (1966; R3xe2x95x90CH3, R4xe2x95x90H), DE 2539300 (1976; R3xe2x95x90H, R4xe2x95x90CH3), WO 99/26962 (R3xe2x95x90CH3, R4xe2x95x90CH3)]. 
A possible synthesis route for compounds of the invention starts with the transformation of compounds of formula II into xcex9414-compounds of formula III using methods described in WO 00/53619. Addition of a suitable carbene intermediate to the xcex9414 double bond results in a (14xcex2,15xcex2,17xcex2)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-ol derivative [Helquist. P., in Comprehensive Organic Synthesis, Vol. 4, p. 951, Pergamon Press, Oxford, N.Y. (1991); Nair, V., ibid., Vol. 4, p. 999 (1991); Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, Inc., 1989, p. 71]. Oxidation of the 17-hydroxy group produces a (14xcex2,15xcex2)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-one derivative (for oxidations, see Hudlicky, M., Oxidations in Organic Chemistry, ACS Monograph 186, Washington, D.C., 1990) which serves as starting material for the introduction of the 17-carbinol fragment.
The conversion of 17-oxo to 17-(CH2OH) can be accomplished in several ways:
(a) 1: Wittig or Peterson reaction to a 17-methyleneestra-1,3,5(10)-triene derivative [Maercker, A., in Org. Reactions 14, p. 270, Wiley, New York, 1965; Ager, D. J., in Org. Reactions 38, p. 1, Wiley, New York, 1990]; 2: hydroboration, for instance by use of 9-BBN, disiamylborane, or thexylborane [see e.g. Zweifel, G. et al, in Org. Reactions 13, p. 1, Wiley, New York, 1963], resulting in the formation of a (17xcex1)-estra-1,3,5(10)-triene-17-methanol derivative and/or the corresponding 17xcex2 isomer.
(b) 1: Conversion of the 17-ketone to a (17xcex2)-spiroestra-1,3,5(10)-triene[17,2xe2x80x2]oxirane by reaction with e.g. trimethylsulfonium iodide/n-BuLi [Corey, E. J. et al, J. Am. Chem. Soc. 87, 1353 (1965)]; 2: (Lewis)acid-catalyzed isomerization of the 17xcex2-oxirane to 17xcex1-formyl [Rickborn, B., in Comprehensive Organic Synthesis, Vol. 3, p. 733, Pergamon Press, Oxford, N.Y. (1991)]; 3: reduction of 17xcex1-formyl to 17xcex1-(CH2OH).
(c) 1: Conversion of the 17-ketone to a 17-methylene compound; 2: epoxidation with e.g. a peroxy acid, such as m-chloroperbenzoic acid, to a (17xcex2)-spiroestra-1,3,5(10)-triene[17,2xe2x80x2]oxirane; 3: (Lewis)acid-catalyzed isomerization to 17xcex1-formyl as described under (b); 4: reduction of 17xcex1-formyl to 17xcex1-(CH2OH).
(d) 1: Conversion of the 17-ketone to a 17xcex2-oxirane as described under (b) and (c); 2: Lewis acid-catalyzed reduction to the 17-methanol steroid [using e.g. NaBH3CN/BF3.Et2O, see: Tone, H. et al, Tetrahedron Lett. 28, 4569 (1987)].
(e) 1: Reaction of the 17-ketone to the 17-cyano steroid by reaction with tosylmethyl isocyanide [TosMIC, see Bull, J. R. et al, Tetrahedron 31, 2151 (1975)]; 2: reduction of the cyano group to formyl by diisobutylaluminum hydride; 3: reduction of the 17-formyl group to 17-(CH2OH).
(f) 1: Wittig condensation with (Ph)3Pxe2x95x90CHOMe; 2: hydrolysis of the resulting enol ether; 3: reduction of 17-formyl to 17-(CH2OH).
(g) 1: Conversion of the 17-ketone to a 17xcex2-oxirane as described under (b) and (c); 2: elimination to a estra-1,3,5(10),16-tetraene-17-methanol derivative; 3: hydrogenation of the xcex9416 double bond.
(h) 1: Conversion of the 17-ketone to the corresponding enol triflate [see e.g. Cacchi, S. et al, Tetrahedron Lett. 25, 4821 (1984)]; 2: palladium-catalyzed alkoxycarbonylation of the latter to a alkyl estra-1,3,5(10),16-tetraene-17-carboxylate [Cacchi, S. et al, Tetrahedron Lett. 26, 1109 (1985)]; 3: reduction of the latter to the corresponding 17-methanol derivative; 4: hydrogenation of the xcex9416 double bond.
(i) 1: Conversion of the 17-ketone to a alkyl estra-1,3,5(10),16-tetraene-17-carboxylate as described under (h); 2: 1,4-reduction, e.g. by hydrogenation or by lithium or sodium in liquid ammonia, to a alkyl estra-1,3,5(10)-triene-17-carboxylate derivative; 3: reduction of the ester to 17-(CH2OH).
Some of these methods (e.g. b,c) result in the stereoselective formation of the 17xcex1-(CH2OH) isomer. Others (e.g. a) may give mixtures which can be separated by chromatography or crystallization.
The (14xcex2,15xcex2,17xcex1)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-methanol derivatives thus obtained are subjected to Birch reduction and subsequent hydrolysis to produce the (14xcex2,15xcex2,17xcex1)-17-(hydroxymethyl)estr-4-ene-3-one derivatives of the invention.
Optionally, a (14xcex2,15xcex2,17xcex1)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde mentioned above can be reacted with an (organometallic) compound of formula R9M in which R9 has the previously given meaning except for hydrogen, and M is Li, Na, K, MgX, ZnX, CeX2, SiR3 or SnR3, to produce a 17-(CHR9OH) derivative which is usually a mixture of C-20 epimers. The latter can be separated whereafter Birch reduction and hydrolysis as described above provides the (14xcex2,15xcex2,17xcex1)-17-(CHR9OH)-14,15-methyleneestr-4-en-3-one derivatives of the invention in which R9 has the previously given meaning except for hydrogen.
Optionally, a (14xcex2,15xcex2,17xcex1)-17-(CHR9OH)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene can be oxidized to obtain a 20-ketone which can then be reacted with an (organometallic) compound of formula R10M, R10 having the previously given meaning except for hydrogen, and M having the previously given meaning. In that case Birch reduction and hydrolysis will provide 17-(CR9R10OH) derivatives of the invention wherein R9 and R10 have the previously given meaning except for hydrogen.
Optionally, the 20-ketone can be reduced by reaction with LiAlH4, NaBH4 or other reducing agents. In that case, 17-(CHR9OH) derivatives are obtained of inverted stereochemistry at C-20. Epimerization at C-20 can also be accomplished by means of a Mitsunobu reaction [Dodge, J. A. et al, Bioorg. and Med. Chem. Lett. 6, 1 (1996)], or by treatment with methanesulfonyl chloride or p-toluenesulfonyl chloride followed by reaction with an oxygen nucleophile [e.g. potassium superoxide, see Corey, E. J. et al, Tetrahedron Lett. 3183 (1975)]. Optionally, a (14xcex2,15xcex2,17xcex1)-3-methoxy-14,15-methyleneestra-2,5(10)-diene-17-methanol derivative, i.e. the product obtained after the Birch reduction, can be oxidized to the corresponding 17-carboxaldehyde. Reaction with a compound of formula R9M as described above and hydrolysis affords the 17-(CHR9OH) derivatives of the invention as already described above. This reaction sequence allows the introduction of substituents R9, and analogously, R10, which would not survive a Birch reduction. Optionally, the 3-methoxy-2,5(10)-diene might also be converted to a more stable system, e.g. a 3,3-dimethoxyestr-5(10)-ene derivative or a estr-4-en-3-one cyclic 1,2-ethanediyl (dithio)acetal derivative, prior to oxidation and reaction with R9M, and so on.
Compounds of formula I with substituents at C-3, C-4, C-7, C-11, C-13, C-1xe2x80x2, C-16 and C-17 other than those described under the definition of formula II, or compounds with R11 other than hydrogen, or compounds without double bonds in the steroid nucleus, or with unsaturations other than a xcex944 double bond, can be prepared as follows.
Compounds of the invention in which R1 is (H,H), (H,OR), NOR, and R is H, (C1-6) alkyl, or (C1-6) acyl can be prepared from compounds of formula I in which R1 is oxo.
Compounds in which R2 is (C1-6)alkyl are obtained from compounds of formula I in which R2 is hydrogen.
Compounds with substituents R3 other than hydrogen can be prepared from e.g. (7xcex1,17xcex2)-7-ethenyl-17-hydroxyestr-4-en-3-one which can be prepared by copper(I)-catalyzed 1,6-addition of vinyllithium or a vinylmagnesium compound to e.g. (17xcex2)-17-(acetyloxy)estra-4,6-diene-3-one [Syntex, DE 1143199 (1963)]. Conversion to (7xcex1)-7-ethenyl-3-methoxyestra-1,3,5(10)-trien-17-one and construction of the functionalized and/or unsaturated side-chain at C-7 from 7-ethenyl are carried out using standard methods, and introduction of the 14xcex2,15xcex2-methylene group and the side-chain at C-17 are accomplished as described above. The precise sequence of reaction steps needed for these operations, and for the Birch reduction and the hydrolysis of the resulting estra-2,5(10)-diene, is dictated by methods common in synthetic strategy.
Compounds with substituents R4 other than hydrogen or (C1-6) alkyl can be obtained from e.g. (11xcex2)-11-(hydroxymethyl)-3-methoxyestra-1,3,5(10)-trien-17-one cyclic 1,2-ethanediyl acetal [van den Broek, A. J. et al, Steroids 30, 481 (1977)], or 3-methoxyestra-1,3,5(10)-triene-11,17-dione cyclic 17-(1,2-ethanediyl acetal) [van den Broek, A. J. et al, Recl. Trav. Chim. Pays-Bas 94, 35 (1975)].
Compounds in which R5 is e.g. ethyl can be prepared from e.g. 13-ethylgon-4-ene-3,17-dione [Brito, M. et al, Synth. Comm. 26, 623 (1996)].
16-Substituted compounds can be obtained via alkylation at C-16 of a (14xcex2,15xcex2)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-one derivative.
17xcex2-Alkylated compounds of formula I can e.g. be obtained via alkylation of a alkyl (14xcex2,15xcex2,17xcex1)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-carboxylate. Compounds of formula I in which R8 is hydroxy, (C1-6) alkoxy, or halogen can be prepared from a (17xcex2)-spiroestra-1,3,5(10)-triene[17,2xe2x80x2]oxirane.
Compounds of the invention in which R11 is SO3H or (C1-15) acyl are obtained from compounds of formula I in which R11 is hydrogen.
Compounds of the invention without unsaturations in the steroid nucleus are produced from xcex944 compounds wherein R1 is oxo.
Compounds of the invention having xcex945(10) double bond, or a xcex944.9 diene system are produced from the xcex942.5(10) dienes obtained after the Birch reduction.
Compounds having a xcex9411 double bond can be prepared from e.g. estra-4,11-diene-3,17-dione [Broess, A. I. A. et al, Steroids 57, 514 (1992)].
The invention will be further explained hereinafter with reference to the following Examples.